tbuckley/cabot-search huggingface dataset:
A pilot trial of neoantigen DNA vaccine in combination with nivolumab/ipilimumab and prostvac in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Koral Shah, Aravinda Ganapathy, Ariel Borkowski, Nakul Shah, Dhruv Bansal, Rachel Beck, Eric Marshall Knoche, Joel Picus, Melissa Andrea Reimers, Bruce J. Roth, James L. Gulley, Robert Schreiber, Russell Kent Pachynski
Journal: Journal of Clinical Oncology (2022)

5068 Background: Treatment with immune checkpoint blockade (ICB) alone results in suboptimal response rates in prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self-antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens have been correlated with favorable clinical outcomes. Thus, we hypothesized that the combination of shared antigen and neoantigen vaccines with dual ICB will induce robust immune responses and improve clinical outcomes. Methods: This Phase I clinical trial (NCT03532217) enrolled patients from 2018-2021. Eligible patients had histologically confirmed high risk mHSPC, must have completed a course of docetaxel and received continuous androgen deprivation therapy. Patients were treated with Prostvac-VF in combination with ipilimumab/nivolumab within 60 days of the last docetaxel dose. Then, patients were continued on monthly nivolumab with their personalized neoantigen vaccine administered via intramuscular electroporation. The primary objectives of this study were to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure free survival, milestone overall survival (OS), PSA responses, and radiographic progression free survival. Results: Nineteen patients were enrolled and treated on trial, and feasibility was shown with 15 (79%) receiving neoantigen vaccines. Four patients did not receive neoantigen vaccines (2 for progressive disease, 2 for ICB toxicity). Treatment was well-tolerated with only 2 (2.4%) grade 3 treatment related adverse events (TRAEs) of colitis, and no grade 4+ TRAEs. The common grade 1-2 TRAEs were diarrhea (10%), injection site reactions (10%), rash (7.4%), and fatigue (6%). Median follow-up to date is 22.6 (11.3-39.6) months, with median OS not yet reached and 2 year milestone OS of 75%. Six (31.5%) patients had PSA progression per PCWG2 criteria while on treatment, with the median time to PSA progression not yet reached for the total population. Increases in activation/co-stimulatory/co-inhibitory seen after treatment with Prostvac/ICB, suggest immune priming. Sample collection is complete and immune correlative analyses are ongoing. Final safety/tolerability and preliminary correlative and clinical outcomes will be reported. Conclusions: This is the first clinical trial evaluating the use of personalized neoantigen vaccines in a combination immunotherapeutic approach in mHSPC patients. Clinical trial information: NCT03532217.
Serum glycoproteomic signatures and association with survival in patients with bone and soft tissue sarcoma treated with immune-checkpoint inhibitor therapy.
Authors: Danie Serie, Chad Pickering, Rachel Rice, Maurice Wong, Hector Huang, Maya Kansara, Subotheni Thavaneswaran, Mandy L. Ballinger, Lucille Sebastian, David Morgan Thomas, Klaus Lindpaintner
Journal: Journal of Clinical Oncology (2022)

11546 Background: Glycosylation is one of the most ubiquitous and functionally important forms of post-translational modification. The role of differential glycosylation in serum proteins has so far been limited by the technical complexity inherent in generating and interpreting this information. InterVenn has built a novel platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine, allowing for highly scalable and reproducible interrogation of glycoproteins with site- and glycan-specificity. Methods: Using this platform, we interrogated 519 glycopeptide (GP) biomarkers derived from 70 serum proteins in pre-treatment samples from a cohort of 103 individuals (56 females, 47 males, age ranging from 18 to 84 years) presenting with one of 20 solid cancer types. All patients were treated with durvalumab and tremelimumab immune checkpoint inhibitor (ICI) therapy. Median follow-up for overall survival (OS) was 11.4 months, with 70 events total observed. OS associations were assessed for individual GPs via Cox regression models and leave-one-out-cross-validation (LOOCV) was employed to generate penalized multivariable prediction scores. Notably, 43 patients had a primary diagnosis of bone and soft tissue sarcoma, and stratified analyses were carried out in this population. Results: We identified 154 biomarkers significantly associated with OS in the full dataset after adjusting for multiple comparisons (FDR &lt; 0.05). Of these, 7 were statistically significant at p &lt; 0.01 in the sarcoma-only subset. LOOCV models built in all cancer types resulted in held-out scores that discriminated those likely to exhibit long-term survival post-ICI therapy from those unlikely to benefit (HR = 4.0, p = 4.91E-08, with 4 GPs included in the final model). Furthermore, LOOCV models including only sarcoma patients demonstrated even stronger predictive attributes (HR = 8.22, p = 2.10E-05, employing 2 glycopeptides). All 9 sarcoma patients with extreme glycosylation signatures for prediction of poor survival displayed quick clinical progression with little benefit from ICI therapy. Relative signal strength and comparative analyses demonstrated strong histotype-specificity inherent in the biomarkers employed for sarcoma vs all cancers. Conclusions: Our results indicate that glycoproteomic liquid biopsy holds potential as a predictive biomarker for identifying sarcoma patients who will derive the greatest benefit from ICI therapy.
Clinical effectiveness of second-line TKI plus PD-1 following targeted therapy in patients with metastatic non-clear cell renal cell carcinoma: A real-world study.
Authors: Jun Wang, Zhiling Zhang, Wensu Wei, Zhiyong Li, Hui Han, Shengjie Guo, Zhiyong Li, Pei Dong
Journal: Journal of Clinical Oncology (2022)

e16523 Background: Non-clear cell renal carcinoma (nccRCC) usually had a poorer response to tyrosine kinase inhibitors (TKIs) due to its heterogeneity and rarity. The combination of immunotherapy with TKIs has shown promising efficacy in ccRCC. However, for nccRCC failed standard first-line TKI therapy, the second-line option is still limited. This real-world study aimed to evaluate the efficacy of immune-targeted combination therapy versus TKI monotherapy as the second-line regimen in patients with metastatic nccRCC who failed first-line TKI therapy. Methods: Demographic and clinicopathological data of patients with metastatic nccRCC who were admitted into the Sun Yat-sen University Cancer Center between October, 2011 and September, 2020 were retrospectively collected. All patients failed in first-line TKI therapy and received second-line TKI alone (TKI group) or TKI plus PD-1 therapy (combination group). Efficacy including the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) was calculated. The differences on baseline characteristics and efficacy between the two groups were compared. Results: Totally 67 patients were included, with a median age of 50 (interquartile 37-60) years. The median follow-up time was 32.7 (interquartile 21.6-53.0) months. The overall ORR, DCR was 37.3% and 56.7%, respectively. The overall second-line PFS was 7.2 (95% CI: 5.8-8.5) months and OS was 53.2 (18.4-88.0) months. Baseline characteristics between the combination group (n = 45) and the TKI group (n = 22) did not differ significantly except that the combination group had more proportion of liver metastasis (20.9% vs 4.5%, P = 0.025). The combination group had a significantly longer PFS compared with the TKI group [median PFS (95% CI): 9.2 (6.4-12.0) vs 5.2 (2.9-7.5) months, P = 0.001]. Similarly, ORR (48.9% vs 13.6, P = 0.005) and DCR (71.1% vs 27.3%, P = 0.001) was remarkably improved in the combination group. The superior efficacy over TKI monotherapy was more prominent in the younger (&lt; 60 years), male, and patients with lower KPS, IMDC intermediate/poor-risk, non-hereditary RCC and multiple metastatic sites. Conclusions: Immune-targeted combination therapy was effective in the treatment of metastatic nccRCC who failed first-line TKIs.[Table: see text]
Oncometabolite profiling identifying estrogen-responsive genes in breast cancer.
Authors: Joyeeta Talukdar, Tryambak Pratap Srivastava, Gayatri Gogoi, Avdhesh Rai, Ruby Dhar, Subhradip Karmakar
Journal: Journal of Clinical Oncology (2022)

e13611 Background: Metabolomic profiling in breast cancer (BC) is an emerging avenue to identify clinically actionable biomarkers as well as targeted therapeutics. Altered metabolic pathways has been identified in BC. Studies have discovered an association between oncometabolite levels, DNA methylation and other epigenetic changes, with prognosis in BC. Changes in cancer cells metabolism may thus indicate disease aggressiveness and its response to therapy. Methods: An in-silico based oncometabolite profiling was performed in ER +ve and TNBC (ER-/PR-/Her2-) data sets using NCBO-GEO tools. . Inclusion criteria included studies on Human subjects, having at least 2 ER+ PR+ and TNBC samples. After manually filtering the top 250 most significant differentially expressed genes in all studies, those with clear metabolic functions as per the GO category were pooled together, which included both the overexpressed and downregulated genes. 15 unique genes were cherry-picked and taken for further analysis out of which six were downregulated, and nine were upregulated. The identified genes harbouring ERE in their upstream 1000bp region were further analysed to identify CpG islands. In addition, we also performed a Bio-Reader based Text Mining Tool to streamline Pubmed abstracts with the positive strings “oncometabolite,” “breast cancer,” “stem cells” “survival”. We also queried against negative strings “sequencing,” “mutations,” “infections,” “drug-resistance” to develop a list of highly focused abstracts. Results: Novel estrogen-regulated oncometabolite that were differentially expressed in ER+ve vs TNBC BC were identified. Further, we reinforced the fact that 4 out of 7 targets had upstream CpG islands within 1000bp n Both upregulated AMY2A, B3GNT5, PNPLA3 and 2HG whereas and downregulated genes in PLCD4, FBP1 and CA12 along with one target identified from the literature were selectively expressed in ER+ve BC. Conclusions: Our study has identified estrogen-responsive metabolic genes involved in BC. We are currently validating our results in a wet lab setup from breast cancer patient samples. Validated targets may be tested for therapeutic intervention in BC.
Identifying predictors of equitable gender representation among hematology and oncology fellowship programs.
Authors: Sasirekha Pandravada, Praneet Mylavarapu, Jacob D. Bitran
Journal: Journal of Clinical Oncology (2022)

11055 Background: While gender disparities have largely been bridged among hematology and oncology fellows at the national level, there exist many individual fellowship programs that still have marked gender disparity. Our study is the first to examine gender differences among fellows at an institutional level in order to model characteristics of hematology and oncology programs that lead to more equitable gender representation. Methods: For each of the 148 hematology or oncology fellowship programs listed in the Fellowship and Residency Electronic Interactive Database, we collected data on gender, faculty academic rank, and fellow postgraduate year as listed on individual program websites. Further, a program was identified as an academic center if it had an affiliated medical school. Zip code data was used to identify geographic region, local population density, and racial diversity of each program’s surrounding neighborhood. Multiple linear regression was used to model which factors contributed to a program having a higher percentage of female fellows. Results: 3600 faculty and 1488 fellows were included in the analysis. While women were well represented nationally among fellows (46.4%), 52.4% of fellowship programs had fewer than 50% women, and 28.6% of programs had fewer than 35% women. An individual program was more likely to have more female fellows if it had a higher percentage of female assistant professors (p&lt;0.01), associate professors (p&lt;0.01), assistant professors overall (p&lt;0.01), a female program director (PD) or associate program director (APD) (p=0.02), and a designation as an academic center (p&lt;0.01). Notably, the percentage of female full professors had no significant impact (p=0.11) on whether a program was likely to have more female fellows. Conclusions: While women are well represented nationally among hematology and oncology fellows, nearly one in three fellowship programs still have significant gender disparity. Our multivariate model identified several significant factors that predict whether a program was likely to have gender parity among fellows: a higher percentage of female assistant professors, associate professors, assistant professors overall, a female PD or APD, and a designation as an academic center. Whether these factors together highlight the importance of accessible mentorship or direct female faculty role models requires further study. However, by beginning to identify these significant factors, we hope to aid fellowship programs focus efforts when trying to achieve equitable gender representation.[Table: see text]
The impact of virtual live education on the competence and knowledge of gynecologists caring for ovarian cancer patients.
Authors: Vanessa Carranza, Bryan Carson Taylor, Susan H. Gitzinger, Joan B. Fowler, Jessica Hall
Journal: Journal of Clinical Oncology (2022)

e23003 Background: About 35% of ovarian cancer patients in the US have geographic-related disparities in their access to gynecologic oncologists. This disparity becomes more apparent as advances in the treatment of ovarian cancer continues to improve, particularly in regard to maintenance therapy (e.g., PARP inhibitors). Thus, it is critical for gynecologists who are most likely to see these patients over the span of their lives, have an intimate understanding of the management of these patients. Methods: CEC Oncology developed an educational initiative presented at four American College of Obstetricians and Gynecologists District Meetings, targeting obstetricians, gynecologists, and other health professionals. Education focused on PARP inhibitors in ovarian cancer, identification of those eligible for genetic testing and counseling, and strategies to improve patient outcomes. Evaluations were collected from attendees attending the District Meetings to assess impact on practice, increased competency, and intent to make a change in practice. This was objectively assessed by analyzing pre-test, post-test, and follow-up survey data (sent 4-6 weeks post-activity). Chi-square analysis was conducted with a priori significance set at 0.05. Results: A total of 183 clinicians were educated, practicing in academic settings (44%), community hospital settings (24%), private practice (25%), and government (7%). Attendees were asked case questions at baseline, immediately after the activity, and 4-6 weeks after the activity to assess knowledge about the DNA damage response pathway, genetic testing guidelines, and management of therapy toxicities. Knowledge increased from pre- to post-test and from pre-test to follow-up for all topics, with the greatest increase in the management of adverse events (41% increase from pre- to post-test; 50% increase from pre-test to follow-up; P&lt; 0.01). Additionally, there was a 22% and 24% increase in confidence in identifying patients eligible for germline genetic testing and in recognizing toxicities with PARP inhibitors from pre-test to six-week follow-up, respectively. 60% of participants stated that there was a lack of patient education regarding the importance of genetic testing and counseling. At follow-up, 100% stated that they had educated patients on genetic testing and counseling, highlighting the value of educating gynecologists on this topic. Conclusions: Attendees of this educational initiative were eager to take back the knowledge learned to their clinical practices. While there was a measurable increase in knowledge with regard to different ovarian cancer related topics, educational gaps remain. Collectively, this particular audience stated that they care for &gt; 1,000 ovarian cancer patients, elucidating the need for OB/GYNs to feel more comfortable regarding PARP inhibitor toxicities, as they become more prevalent in practice.
Cellworks singula therapy response index (TRI) predicts clinical outcomes for esophageal adenocarcinoma: MyCare-004.
Authors: Elizabeth Catherine Smyth, Drew Watson, Barbara Nutzinger, Michael P Castro, Shweta Kapoor, Samiksha Avinash Prasad, Swaminathan Rajagopalan, Calvin Cheah, Prashant Ramachandran Nair, Aftab Alam, Ginny Devonshire, Nicola Grehan, Rakhi Purushothaman Suseela, Anuj Tyagi, Ashish Kumar Agrawal, Humera Azam, Mohammed Sauban, Anusha Pampana, Michele Dundas Macpherson, Rebecca C. Fitzgerald
Journal: Journal of Clinical Oncology (2022)

4064 Background: Computational biological modeling reveals many dysregulated signaling pathways responsible for hallmark behaviors of cancer and variable drug response in the population. A mechanistic model created for each patient using comprehensive genomic inputs can biosimulate downstream molecular effects of cell signaling and drugs for each patient’s personalized in silico virtual disease model. Singula TRI is designed to predict the outcome of specific therapies with a continuous TRI Score, 0 to 100, for each patient’s unique genomic network. Methods: TRI’s ability to predict Overall Survival (OS), Disease Free Survival (DFS) and Mandard – tumor regression grade (TRG) was prospectively evaluated in a retrospective cohort of gastroesophageal adenocarcinoma (GEA) from UK OCCAMS consortium. Random sampling stratified by clinical factors was used to split the data into independent training (N = 140) and validation (N = 131) subsets. Multivariate Cox Proportional Hazard (PH) and Proportional Odds models were used to predict survival and pathological response as a function of the pre-defined TRI and clinical thresholds compared with standard clinical factors. Results: 271 GEA patients were selected who had pre-chemo treated biopsies with 50x whole genome sequencing from the OCCAMS International Cancer Genome Consortium study. The median age was 65.6 years, 234 male and 30 female, with deceased median OS of 21.9 months and living of 49.9 months. There were 35 T2, 215 T3, 70 N0, 126 N1, 62 N2 and 266 M0. Patients were treated with physician prescribed chemotherapy treatments (PPT) according to UK clinical guidelines (SC). Biosimulation revealed that 99% of these tumors had deficiency in DNA repair genes. Other pathways included amplification of multi-drug resistance pumps, TP53 mutations and aberrations of the PI3K/AKT pathway genes. The table shows that TRI provides additional predictive information for OS and DFS beyond PPT and standard clinical factors. TRI was also predictive of TRG in univariate analysis. TRI scores were also generated for 82 alternate therapies for each patient enabling selection of optimal therapies with estimates of improvements in median OS and DFS compared to SC. Conclusions: In this cohort of patients, Cellworks Singula TRI was predictive of survival and TRG beyond clinical factors. These positive results suggest the utility of biosimulation-informed therapy selection to improve survival of GEA and validation in prospective clinical studies is warranted.[Table: see text]
The professional seniority affects the clinical application of total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Elif Şenocak Taşçi, Erman Aytac, Mırac Ajredini, Arda Ulaş Mutlu, Ibrahim Yildiz, Leyla Ozer
Journal: Journal of Clinical Oncology (2022)

e15590 Background: Total neoadjuvant therapy (TNT) integrates whole planned systemic chemotherapy within standard neoadjuvant protocols either before or after radiotherapy for locally advanced rectal cancer (LARC). Preference of neoadjuvant treatment type may vary among the medical oncologists. This study aimed to evaluate impact of professional seniority on TNT approach for LARC. Methods: A 20-item questionnaire was presented to medical oncologists as a cross-sectional survey during a national oncology congress via tablets. The evaluation was stratified by position; early-career oncologists (ECOs) and seniors. 2 questions were about experience regarding rectal cancer treatment. 5 questions were about physicians’ choice of screening and treatment in LARC and the factors affecting their treatment choices. 13 questions were about TNT approach (the sequencing of treatment, denominators of sequencing, chemotherapy choice, treatment response evaluation, operation preferences, adjuvant treatment and its denominators). Results: 189 medical oncologists were included (62.4% (n = 118) ECOs). An endorectal ultrasound was significantly preferred by the seniors (p = 0.039) in addition to conventional staging tools. 65.6% (n = 124) of the participants preferred long-course chemoradiation as their favorite neoadjuvant treatment approach. External sphincter invasion, threatened circumferential resection margin (CRM) and clinical stage were the most common denominators of TNT regardless of experience. ECOs favored short-course RT (p = 0.009) while the seniors chose long-course chemoradiotherapy (p = 0.041) as the index step of TNT. 57% (n = 108) of the physicians preferred to monitor treatment response for TNT at 8-weeks periods. Almost half of the participants (47.1%) reported pathological complete response (pCR) rates between 25-50% with TNT in their clinical practice. The physicians who prefer to give adjuvant treatment after completion of TNT make individualized decisions when surgical pathology reveals non-pCR, CRM and lymph node involvement. There was a significant difference between the ECOs and seniors (63.6 vs 45.1%, p = 0.013) in terms of choosing the adjuvant chemotherapy based on CRM positivity. Majority of the senior medical oncologists (88%) and ECOs (76.3%) agree that TNT should be the standardized neoadjuvant treatment approach for LARC. The preferred adjuvant chemotherapy after TNT was capecitabine-oxaliplatin (51.1%) or capecitabine alone (46%). Conclusions: TNT for LARC is well accepted among the medical oncologists and the professional seniority seems to affect its clinical application.